Superoxide anion is formed by macrophages and polymorphonuclear leukocytes, also known as neutrophils as a byproduct of oxygen metabolism. Macrophages and neutrophils are distributed throughout most tissues and play a role in inflammation, in host defense, and in reactions against a number of autologous and foreign substances. As major players in the inflammatory response, they are attracted to sites of injury or disease by cytokines released at these sites. While superoxide anion can function as a microbicidal agent that helps degrade tissue damaged from external or internal trauma, it can also have destructive effects. The presence of superoxide anion can lead to the formation of other reactive and tissue-damaging species such as HOCl and H.sub.2 O.sub.2. In the presence of Fe.sup.2+, H.sub.2 O.sub.2 can proceed to form hydroxyl radical which can be highly destructive to surrounding tissue.
Superoxide anion is produced in response to inflammation or of non-inflammatory conditions, such as adult respiratory distress syndrome, and can lead to significant tissue injury (S. L. Leib et al., J. Clin. Invest. 98(1 1):2632-2639 (1996); R. A. Miller et al., J. Invest. Med. 43(1):39 (1995); and J. Jackson et al., Hematology/Oncology Clinics of North America 2(2):317-34 (1988)). Inflammation accompanies a variety of disorders, including eczema, inflammatory bowel disease, rheumatoid arthritis, asthma, psoriasis, ischemia/reperfusion injury, ulcerative colitis and acute respiratory distress syndrome. These disorders can be chronic and, in severe cases, life-threatening. In addition, acute inflammation can follow a heart attack or stroke and often results in irreparable damage to surrounding tissue.
Exposure of tissues to superoxide anion radical can lead to oxidative stress and tissue damage, which can contribute to the development of pathological conditions. Superoxide anion can act as a carcinogen causing oxidant-induced DNA sequence changes that affect the activities of proto-oncogenes and supressor genes and activating cellular kinases to promote cell growth (Cerutti and Trump, Cancer Cells 3:1-7 (1991)). The production of superoxide anion and other free radicals can lead to demyelination or neuronal death and conditions such as multiple sclerosis, the deterioration of cognitive function with aging, dementia, amyotropic lateral sclerosis ("ALS"), Alzheimer's disease, Parkinson's disease, and other degenerative neuropathies. (Keller and Mattson, Rev. Neurosci. 9:105-116 (1998); McGeer and McGeer, J. Neural. Transm. Suppl. 54: 159-166 (1998); Markesbery, Free Radic. Biol. Med. 23:13447 (1997); Jenner and Olanow, Neurology 47(6Suppl 3):S161-70 (1996); Evans, Br. Med. Bull. 49:577-87 (1993); Joseph, Integr. Physiol. Behav. Sci. 27:216-27 (1992)).
Current therapies for conditions that result from oxidative tissue damage are either non-existent or fraught with drawbacks. First, while these therapies may act to reduce the degree of tissue swelling that accompanies inflammation, these therapies do not inhibit the formation of tissue-damaging superoxide anion, H.sub.2 O.sub.2 or HOCl. Second, therapies involving the administration of anti-inflammatory steroids can cause undesirable immunosuppression and, in fact, premature atrophy of the thymus gland. Third, therapies involving a prolonged use of salicylates or other non-steroidal anti-inflammatory drugs can result in gastrointestinal bleeding. Fourth, therapies used for the treatment of asthma that involve repeated and frequent use of bronchiodialators can result in drug tolerance and a need for increased dosages and/or alternative drugs. Therapies for cancer are far fewer in number, have serious drawbacks, and have limited efficacy. Chemotherapy can be highly toxic, resulting in fatigue, vomiting, hair loss, and immunosuppression. Radiation therapy can lead to burns and localized immunosuppression. Excision of cancerous lesions can be highly invasive. Therapies for degenerative neuropathies are virtually non-existent. Although it is possible to use chemicals to slow nerve degeneration, methods for completely halting or reversing the damage have not yet been elucidated.
Thus, there is a clear need for agents that inhibit superoxide anion production, thereby treating or preventing conditions resulting from oxidative tissue damage without causing the above-mentioned, undesirable side-effects.
Phosphatidylinositol 3,4,5-trisphosphate has been isolated from FLPEP-stimulated human neutrophils (A. E. Traynor-Kaplan et al., J. Biol. Chem. 264(26):15668-15673 (1989) and A. E. Traynor-Kaplan et al., Nature 334(6180):353-56 (1988)). It has recently been shown that certain inositol phosphate derivatives including D-myoinositol 3,4,5,6-tetrakisphosphate (A. Vajanaphanich et al., Nature 371:711 (1994); J. M. Uribe et al., J. Biol. Chem. 271(43):26588 (1996); M. T. Rudolf et al., J. Med. Chem. 41 (19):3635-3644 (1998)), and sn-di-O-pahmitoyl-D,L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis(acetoxymethyl)ester (C. Schultz et al., Membrane-penneant, Bioactivatable Derivatives of Inositol Polyphosphates andphosphoinositides, in Phosphoinositides: Chemistry, Biochemistry and Biomedical Applications, K. S. Bruzik, Ed. Am. Chem. Soc., Symp. Ser., 718, 232-243 (1998)) inhibit calcium-mediated chloride secretion. D-myo-Inositol 1,4,5,6-tetrakisphosphate has been shown to inhibit a phosphatidylinositol PI-3 kinase ("PI-3 kinase") signaling pathway in colonic epithelia (Eckmann et al., Proc. Natl. Acad. Sci. USA 94:14456 (1997)). It has also recently been shown that 2,6-di-O-butyryl-myo-inositol 1,2,4,5-octakis(acetoxylmethyl)ester increased the level of Ca.sup.2+ in PC12 cells (C. Schultz et al. (1998), supra). U.S. Pat. No. 5,693,521 to Tsien et al. discloses the use of D-2,3-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis(acetoxymethyl)ester as a second messenger having enhanced cell permeability. International Publication No. WO 98/11901 by Traynor-Kaplan et al. describes various inositol phosphates with enhanced cell permeability that function as either agonists or antagonists of inositol polyphosphates. In addition, other inositol phosphates have been reported (S. Roemer et al., J. Chem. Soc., Perkin Trans. 1, 1683 (1996); International Publication No. WO 96/40695 to Tsien et al.; International Publication No. WO 98/11901 to A. Traynor-Kaplan et al.; Rudolf, M. T. et al., Bioorg. & Med. Chem. Lett., 8:1857 (1998); Jiang, T. et al., J. Biol. Chem. 273:11017 (1998); Li, W., et al., Tetrahedron 53:12017 (1997)).
To the best of Applicants' knowledge, there has been no published report concerning the use of an inositol derivative for inhibiting the production of superoxide anion resulting from the inflammatory response. Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.